We have shown the anticancer drugs affecting the integrity of microtubules induce Bcl2 phosphorylation and loss of function, whereas, anticancer drugs damaging DNA do not. Phosphorylation of Bc12 in drug treated cancer cells occur at G2-M, the phrase of the cell cycle in which this class of drugs is active. Thus, inhibition of polymerization or depolymerization of cellular microtubules by this class of cancer therapeutic drugs cause phosphorylation of Bcl2, abrogating the normal antiapoptotic function of Bcl2 and initiating the apoptotic program in cycling cancer cells. These results are consistent with a normal physiologic role of Bc12 as "guardian of the mitotic spindle". A corollary to their observations is that mutations of critical serine residues of Bc12 should prevent Bc12 phosphorylation and should make cell resistant to drugs causing Bc12 phosphorylation and apoptosis. We propose to answer this questions and to determine whether tumor cell lines resistant to taxol and to vinblastine/vincristine have Bc12 mutations or whether fail to phosphorylate Bc12 in response to these drugs at serine residue(s). If we find that drug resistant cell lines fail to phosphorylate Bc12 because of mutations of Bc12 or of a Bc12 kinase, we will investigate primary tumors that are resistant to these drugs. Finally, we propose to construct transgenic mice expressing mutated Bc12 proteins in different tissues to determine the biologic consequences of the inability to phosphorylate Bc12 in B cells, T cells and mammary tissue. The prediction is that overexpression of Bc12 resistant to phosphorylation will lead to genomic instability.